What are examples of CYP (Cytochrome P450) inhibitors and how do they affect medication levels?

From the Guidelines

CYP inhibitors are substances that block cytochrome P450 enzymes, and examples include ketoconazole, erythromycin, fluoxetine, grapefruit juice, and ritonavir, which can increase blood levels of medications metabolized by these pathways, potentially causing toxicity or enhanced effects. When these inhibitors are present, medications normally broken down by CYP enzymes remain in the bloodstream longer and at higher concentrations. Some key points to consider when dealing with CYP inhibitors include:

• The strength of inhibition varies, with some medications like fluconazole causing moderate inhibition and others like ketoconazole producing strong inhibition 1.
• The timing of inhibition also differs, with some effects occurring immediately and others developing over days.
• Patients should always inform healthcare providers about all medications and supplements they take to avoid potentially dangerous drug interactions involving CYP inhibition. Some specific examples of CYP inhibitors and their effects include:
• Clarithromycin (a CYP3A4 inhibitor) taken with simvastatin (metabolized by CYP3A4) can increase statin levels 10-fold, raising the risk of muscle damage 1.
• Diltiazem is a substrate of CYP3A4 (major) and a moderate CYP3A4 inhibitor, and should be used with caution with certain medications such as apixaban, itraconazole, and bosutinib 1.
• Verapamil is a moderate CYP3A4 inhibitor and also inhibits P-glycoprotein, and should be used with caution with certain medications such as dofetilide, itraconazole, and simvastatin 1. It's worth noting that the most recent and highest quality study on this topic is from 2016, which provides a comprehensive list of CYP inhibitors and their potential interactions with other medications 1. Overall, it's essential to carefully consider the potential interactions between CYP inhibitors and other medications to minimize the risk of adverse effects and ensure optimal treatment outcomes.

From the FDA Drug Label

Drugs that Affect Clarithromycin Drug(s) that Affect the Pharmacokinetics of Clarithromycin Recommendation Comments Antifungals: Itraconazole Use With Caution Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions

• CYP inhibitors are drugs that decrease the activity of the cytochrome P450 enzyme system, which can lead to increased levels of other medications.
• Examples of CYP inhibitors include:
  • Itraconazole (an antifungal) which may increase the plasma concentrations of clarithromycin 2
  • Atazanavir and Ritonavir (protease inhibitors) which can decrease the concentrations of 14-OH clarithromycin
• These inhibitors can affect medication levels by increasing the concentration of the medication in the body, which can lead to increased or prolonged adverse reactions.
• Patients taking these medications concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.

From the Research

CYP Inhibitors

• CYP inhibitors are drugs that inhibit the activity of cytochrome P450 enzymes, which are involved in the metabolism of many medications 3.
• Examples of CYP inhibitors include:
  • Ketoconazole: a potent CYP3A4/5 inhibitor, although its use has been limited due to safety concerns 4, 5, 6.
  • Itraconazole: an alternative to ketoconazole, which has been recommended by regulatory agencies for use in clinical drug-drug interaction studies 4, 6, 7.
  • Clarithromycin: another alternative to ketoconazole, which has been evaluated for its potential to inhibit CYP3A4 4, 5, 6.
  • Ritonavir: a strong CYP3A4 inhibitor, which has been shown to produce inhibition equivalent to or greater than ketoconazole 5.

Effects on Medication Levels

• CYP inhibitors can increase the levels of medications that are metabolized by the cytochrome P450 enzymes, which can lead to increased efficacy or toxicity 3.
• The extent of the interaction depends on various factors, including the specific CYP inhibitor and medication involved, as well as patient-related factors such as age and pre-existing medical conditions 3.
• CYP inhibitors can also affect the pharmacokinetics of medications by inhibiting transporters, such as P-glycoprotein, which can lead to changes in drug absorption and distribution 4.